Retinoblastoma is the most common neoplasm of the eye in childhood, and represents 3% of all childhood malignancies. Retinoblastoma is a cancer of the very young; two-thirds are diagnosed before 2 years of age and 95% before 5 years. Retinoblastoma presents in 2 distinct clinical forms: (1) a bilateral or multifocal, heritable form (25% of all cases), characterized by the presence of germline mutations of the RB1 gene; and (2) a unilateral or unifocal form (75% of all cases), 90% of which are nonhereditary. The treatment of retinoblastoma is multidisciplinary and is designed primarily to save life and preserve vision.
Key points
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Retinoblastoma is the most common cancer of the eye in children, accounting for 3% of all childhood malignancies. Retinoblastoma affects very young children: two-thirds of the cases are diagnosed before 2 years of age, and more than 90% before 5 years.
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Two clinical forms are identified: (1) unilateral retinoblastoma, which accounts for approximately 75% of the cases; and (2) bilateral retinoblastoma, which accounts for 25% of the cases. Patients with bilateral disease carry a germline mutation of the RB1 gene; this mutation is inherited from an affected parent in 25% of the cases, and results from a de novo mutation in utero in 75% of the cases.
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Treatment of retinoblastoma is risk adapted. Factors to be considered in the treatment decisions include intraocular and extraocular stage, laterality, and potential for vision. Ocular salvage treatments include systemic or intra-arterial chemotherapy, aggressive focal treatments (photocoagulation, thermotherapy, cryotherapy, and brachytherapy), and external beam radiation therapy.
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Children with bilateral disease are at high risk of developing second malignancies and therefore need to be followed closely. Radiation therapy is avoided whenever possible in this group of children.
Introduction
Retinoblastoma is the most common neoplasm of the eye in childhood, representing 2.5% to 4% of all pediatric cancers. The average age-adjusted incidence rate of retinoblastoma in the United States and Europe is 2 to 5 per million children (approximately 1 in 14,000–18,000 live births). Retinoblastoma is a cancer of the very young; two-thirds are diagnosed before 2 years of age, and 95% before 5 years.
Retinoblastoma presents in 2 distinct clinical forms: (1) a bilateral or multifocal, heritable form (25% of all cases), characterized by the presence of germline mutations of the RB1 gene and that may be inherited from an affected survivor (25%) or be the result of a new germline mutation (75%); and (2) a unilateral or unifocal form (75% of all cases), 90% of which are nonhereditary. About 10% of germline cases are unilateral and unifocal; however, in the absence of a positive family history, it is not possible without genetic screening to determine which unilateral cases involve the germ line and are thus capable of being transmitted to the next generation.
Introduction
Retinoblastoma is the most common neoplasm of the eye in childhood, representing 2.5% to 4% of all pediatric cancers. The average age-adjusted incidence rate of retinoblastoma in the United States and Europe is 2 to 5 per million children (approximately 1 in 14,000–18,000 live births). Retinoblastoma is a cancer of the very young; two-thirds are diagnosed before 2 years of age, and 95% before 5 years.
Retinoblastoma presents in 2 distinct clinical forms: (1) a bilateral or multifocal, heritable form (25% of all cases), characterized by the presence of germline mutations of the RB1 gene and that may be inherited from an affected survivor (25%) or be the result of a new germline mutation (75%); and (2) a unilateral or unifocal form (75% of all cases), 90% of which are nonhereditary. About 10% of germline cases are unilateral and unifocal; however, in the absence of a positive family history, it is not possible without genetic screening to determine which unilateral cases involve the germ line and are thus capable of being transmitted to the next generation.
Epidemiology
The incidence of retinoblastoma is not distributed equally around the world. It seems to be higher (6–10 cases per million children) in Africa, India, and among children of Native American descent in the North American continent. The increased incidence in those groups occurs primarily in unilateral cases. Whether these geographic variations are caused by ethnic or socioeconomic factors is not well known. Studies from Mexico and Brazil have documented an inverse correlation between the incidence of retinoblastoma and socioeconomic index, and in more industrialized countries an increased incidence of retinoblastoma has also been associated with poverty and low levels of maternal education.
On a perhaps related note, decreased dietary intake of vegetables and fruits during pregnancy, resulting in decreased intake of nutrients such as folate and carotenoids, which are necessary for DNA methylation and synthesis as well as for retinal formation, has also been associated with an increased risk of unilateral sporadic retinoblastoma. In a case-control study, the risk of developing retinoblastoma was associated with a maternal polymorphism in dihydrofolate reductase ( DHFR 19bpdel), particularly in women taking prenatal synthetic folic acid supplements.
Most germline mutations in sporadic heritable retinoblastoma are paternally derived, and studies have suggested an association between paternal age and occupation and the occurrence of sporadic heritable retinoblastoma. Reports have also suggested an association between retinoblastoma and increased sunlight exposure, air toxics from gasoline and diesel combustion, or in vitro fertilization. In a case-control study of sporadic retinoblastoma, radiological studies of the abdomen leading to scattered radiation exposure of the gonads were associated with an increased risk of bilateral retinoblastoma in a subsequent child.
Biology
In 1971, based on the mathematical analysis of the age at presentation of bilateral (hereditary) and unilateral (mostly nonhereditary) cases of retinoblastoma, Knudson proposed the 2-hit hypothesis, in which 2 mutational events in a developing retinal cell lead to the development of retinoblastoma. This hypothesis was subsequently extended to suggest that the two events could be mutations of both alleles of the RB1 gene. RB1 , located in chromosome 13q14, was identified and cloned in 1986. Its product, pRb, is a key substrate for G1 cyclin-cdk complexes, which phosphorylate target gene products required for the transition of the cell through the G1 phase of the cell cycle. The active pRb functions as a tumor suppressor and is the major gatekeeper to control this critical point in growth regulation. The lack of pRb, or its inactivation, removes the pRb constraint on cell cycle control, with the consequence of deregulated cell proliferation. Biallelic loss of RB1 function is required for tumor development; this loss is germ line and somatic for patients with bilateral disease, and somatic in patients with unilateral disease. However, additional events are required for tumor progression. Approximately two-thirds of tumors have MDM4/MDM2 amplification leading to inactivation of the p53 pathway. RB1 plays an important role in maintaining genomic stability and thus inactivation of the RB1 gene could lead to chromosome instability, allowing secondary and tertiary mutations in key cancer pathways to be rapidly acquired. RB1 has also been implicated in a variety of epigenetic processes; thus, it is also possible that perturbations in the epigenetic landscape may contribute to tumorigenesis in the retina. In support of an epigenetic mechanism, recent whole-genome sequencing and integrated epigenetic analysis of human retinoblastoma revealed that the tumors have stable genomes and several cancer genes were epigenetically deregulated. At least 1 of those epigenetically deregulated genes ( SYK ) is required for retinoblastoma tumor cell survival in vivo (discussed later). In addition, a small proportion of tumors seem to develop in the context of normal RB1 ; amplification of N-MYC has been described in those cases.
Prevention, early detection, and genetic counseling
The successful management of retinoblastoma depends on the ability to detect the disease while it is still intraocular; disease stage correlates with delay in diagnosis. In developing countries, late referrals are strongly associated with orbital and metastatic disease. It is for this reason that eye assessment should be performed in all newborns and at all subsequent health supervision visits by the primary care provider. Retinoblastoma is a unique neoplasm in that the genetic form imparts a predisposition to developing tumor in an autosomal dominant fashion with almost complete penetrance (85%–95%). Most such children acquire the first mutation as a new germline mutation, with only 25% having a positive family history. Genetic counseling is critical to assist parents in understanding the genetic consequences of each form of retinoblastoma and to estimate the risk in relatives. Regardless of the clinical presentation, it is recommended that all patients undergo genetic testing. With the refinement in methods of mutational analysis over the last decade, detection rates have increased to greater than 90% at present. Given the heterogeneity in the site and type of gene defects, no single technology is sensitive and effective, and a multistep approach must be taken. More than 80% of the mutations can be detected with sequencing of the 27 exons of the RB1 using a quantitative multiplex polymerase chain reaction (QMPCR). However, 10% to 20% of the defects are caused by large deletions and therefore deletion scanning and Southern blotting is required for those cases with no detectable mutations by QMPCR. In addition, a small proportion of cases (probably <5%) may result from gene inactivation by promoter methylation, and therefore screening for constitutional methylation should be considered if the other methods do not reveal a mutation.
Clinical manifestations, patient evaluation, and staging
Retinoblastoma is by definition a tumor of young children, and the age at presentation correlates with the risk of bilaterality. Patients with bilateral retinoblastoma tend to present at a younger age (usually before 1 year of age) than patients with unilateral disease (often in the second or third year of life). In more than half of the cases, the presenting sign is leukocoria, which is occasionally first noticed after a flash photograph ( Fig. 1 ). Strabismus is the second most common presenting sign, and usually correlates with macular involvement. Advanced intraocular tumors may become painful as a result of secondary glaucoma. The differential diagnosis of a child presenting with leukocoria includes persistent hyperplastic primary vitreous, retrolental fibrodysplasia, Coats disease, congenital cataracts, toxocariasis, and toxoplasmosis.
A small proportion of patients with bilateral disease (5%–6%) carry a deletion involving the 13q14 locus, which is large enough to be detected by karyotype analysis. In those cases, retinoblastoma is part of a more complex syndrome resulting from the loss of additional genetic material. Patients with the 13q syndrome are characterized by typical facial dysmorphic features, subtle skeletal abnormalities, and different degrees of mental retardation and motor impairment. Dysmorphic features consistently found include thick anteverted ear lobes, high and broad forehead, prominent philtrum, and short nose. A proportion of patients also have overlapping fingers and toes, microcephaly, and delayed skeletal maturation.
Trilateral retinoblastoma refers to the association of bilateral retinoblastoma with an asynchronous intracranial tumor, which occurs in less than 10% of bilateral cases. Tumors comprising trilateral retinoblastoma are primitive neuroectodermal tumors (PNETs) showing varying degrees of neuronal or photoreceptor differentiation, suggesting an origin from the germinal layer of primitive cells. Most of these tumors are pineal region PNETs (pineoblastomas), but in 20% to 25% of the cases the tumors are suprasellar or parasellar. Rare cases of quadrilateral retinoblastoma have been reported, in which bilateral retinoblastoma is associated with both pineal region and suprasellar intracranial primary PNETs. The median age at diagnosis of trilateral retinoblastoma is 23 to 48 months and the interval between the diagnosis of bilateral retinoblastoma and the diagnosis of the brain tumor is usually more than 20 months. Approximately 5% to 8% of patients with bilateral disease develop pineal cysts; these may be a forme fruste of trilateral retinoblastoma.
The diagnosis of intraocular retinoblastoma is usually made without pathologic confirmation. An examination under anesthesia with a maximally dilated pupil and scleral indentation is required to examine the entire retina (see Fig. 1 ). Endophytic tumors are those that grow inward to the vitreous cavity. Because of its friability, endophytic retinoblastoma may seed the vitreous cavity. Exophytic retinoblastoma grows into the subretinal space, thus causing progressive retinal detachment and subretinal seeding. A detailed documentation must be performed of the number, location, and size of tumors; the presence of retinal detachment and subretinal fluid; and the presence of vitreous and subretinal seeds. Wide-angle real-time retinal imaging systems such as RetCam provide a 130° field of view and digital recording, facilitating diagnosis and monitoring.
Additional imaging studies that aid in the diagnosis include bidimensional ultrasonography, computed tomography (CT), and MRI. These imaging studies are particularly important to evaluate extraocular extension and to differentiate retinoblastoma from other causes of leukocoria. CT is helpful to detect calcifications, although its use is generally sparing, in order to limit radiation exposure, particularly in children with bilateral disease. MRI is helpful in working through the differential diagnosis, including Coats disease and other inflammatory conditions, as well as persistent fetal vasculature of hyperplastic primary vitreous. MRI is not particularly useful in the work-up of microscopic or optic nerve involvement. Ultrasonography is useful in the diagnosis of retinoblastoma because it can reveal highly reflective calcifications, when present, and it is used during the course of treatment to monitor tumor size with regard to growth or regression.
Metastatic disease occurs in approximately 10% to 15% of patients, and it usually occurs in association with distinct intraocular histologic features, such as deep choroidal and scleral invasion, or with involvement of the iris, ciliary body, or optic nerve beyond the lamina cribrosa. In these cases, additional staging procedures, including bone scintigraphy, bone marrow aspirates and biopsies, and lumbar puncture, must be performed. In up to one-third of high-risk patients, the synthase of ganglioside GD2 messenger RNA may be detected in the cerebrospinal fluid (CSF) by reverse transcriptase polymerase chain reaction, and it seems to correlate with massive involvement of the optic nerve, the presence of glaucoma at diagnosis, and a high risk of CSF relapse. In general, in the absence of high-risk disorders in patients who have undergone enucleation, and in patients with intraocular disease undergoing ocular salvage therapies, metastatic work-up is usually not necessary. In patients with extraocular disease, the use of immunocytology with GD2 or CRX staining may increase the yield for detection of small clumps of metastatic cells.
The Reese-Ellsworth (R-E) grouping system was the first classification scheme to be widely used to describe intraocular disease. This grouping system was designed to predict the outcome after external beam radiation therapy. It divides retinoblastoma-involved eyes into 5 groups by the size, location, and number of lesions, and by the presence of vitreous seeding ( Box 1 ). However, more recent developments in the conservative management of intraocular retinoblastoma have made the R-E grouping system less predictable of eye salvage, and less helpful in guiding treatment. A new staging system (International Classification of Intraocular Retinoblastoma) has been developed, with the goal of providing a simpler, user-friendly classification more applicable to current therapies. This new system is based on extent of tumor seeding within the vitreous cavity and subretinal space, rather than on tumor size and location, and seems to be a better predictor of treatment success ( Box 2 , Fig. 2 ).
Group I. Very favorable
Ia: solitary tumor smaller than 4 dd at or behind the equator
Ib: multiple tumors, none larger than 4 dd, all at or behind equator
Group II. Favorable
IIa: solitary tumor 4 to 10 dd, at or behind equator
IIb: multiple tumors 4 to 10 dd, at or behind equator
Group III. Doubtful
IIIa: any lesion anterior to equator
IIIb: solitary tumor larger than 10 dd behind equator
Group IV. Unfavorable
IVa: multiple tumors, some larger than 10 dd
IVb: any lesion extending anteriorly to the ora serrata
Group V. Very unfavorable
Va: massive tumors involving more than half the retina
Vb: vitreous seeding
Abbreviation: dd, disk diameter (1.5 mm).
Group A
Small tumors away from foveola and disc
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Tumors less than or equal to 3 mm in greatest dimension confined to the retina, and
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Located at least 3 mm from the foveola and 1.5 mm from the optic disc
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Group B
All remaining tumors confined to the retina
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All other tumors confined to the retina not in group A
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Subretinal fluid (without subretinal seeding) less than or equal to 3 mm from the base of the tumor
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Group C
Local subretinal fluid or seeding
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Local subretinal fluid alone greater than 3 mm to less than or equal to 6 mm from the tumor
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Vitreous seeding or subretinal seeding less than or equal to 3 mm from the tumor
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Group D
Diffuse subretinal fluid or seeding
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Subretinal fluid alone greater than 6 mm from the tumor
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Vitreous seeding or subretinal seeding greater than 3 mm from tumor
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Group E
Presence of any of these poor prognosis features
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More than two-thirds of the globe filled with tumor
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Tumor in anterior segment
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Tumor in or on the ciliary body
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Iris neovascularization
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Neovascular glaucoma
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Opaque media from hemorrhage
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Tumor necrosis with aseptic orbital cellulitis
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Phthisis bulbi
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For patients undergoing enucleation, pathologic staging that incorporates other features that influence the choice of treatment modality and the prognosis, such as choroidal and scleral involvement, optic nerve extension, and presence of metastatic disease, are used. Different staging systems have classically been used, including the Grabowski-Adamson, the St Jude Children’s Research Hospital, the American Joint Commission for Cancer (AJCC), and the International Retinoblastoma Staging System (IRSS). The IRSS is a newly proposed staging system developed by an international consortium of ophthalmologists and pediatric oncologists that incorporates the most important elements of the older systems ( Box 3 ). The AJCC ( Box 4 ) and the IRSS systems seem to be the most reliable for grouping patients according to their risk of extraocular relapse.
Stage 0. Patients treated conservatively.
Stage I. Eye enucleated, completely resected histologically.
Stage II. Eye enucleated, microscopic residual tumor.
Stage III. Regional extension.
- a.
Overt orbital disease
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Preauricular or cervical lymph node extension
- a.
Stage IV. Metastatic disease
- a.
Hematogenous metastasis (without central nervous system [CNS] involvement)
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Single lesion
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Multiple lesions
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- b.
CNS extension (with or without any other site of regional or metastatic disease)
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Prechiasmatic lesion
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CNS mass
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Leptomeningeal and CSF disease
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- a.
Clinical classification (tumor-node-metastasis staging by clinical examination [cTNM])
Primary tumor (T)
TX: primary tumor cannot be assessed.
T0: no evidence of primary tumor.
T1: tumors no more than two-thirds the volume of the eye with no vitreous or subretinal seeding.
T1a: no tumor in either eye is greater than 3 mm in largest dimension or located closer than 1.5 mm to the optic nerve or fovea.
T1b: at least 1 tumor is greater than 3 mm in largest dimension or located closer than 1.5 mm to the optic nerve or fovea. No retinal detachment or subretinal fluid beyond 5 mm from above the base of the tumor.
T1c: at least 1 tumor is greater than 3 mm in largest dimension or located closer than 1.5 mm to the optic nerve or fovea, with retinal detachment or subretinal fluid beyond 5 mm from the base of the tumor.
T2: tumors no more than two-thirds the volume of the eye with vitreous or subretinal seeding. Can have retinal detachment.
T2a: minimal tumor spread to vitreous and/or subretinal space. Focal vitreous and/or subretinal seeding of fine aggregates of tumor cells is present, but no large clumps or snowballs of tumor cells.
T2b: massive tumor spread to the vitreous and/or subretinal space. Massive vitreous and/or subretinal seeding is present, defined as diffuse clumps or snowballs of tumor cells.
T3: severe intraocular disease.
T3a: tumor fills more than two-thirds of the eye.
T3b: 1 or more complications present, which may include tumor-associated neovascular or angle closure glaucoma, tumor extension into the anterior segment, hyphema, vitreous hemorrhage, or orbital cellulitis.
T4: extraocular disease detected by imaging studies.
T4a: invasion of optic nerve.
T4b: invasion of the orbit.
T4c: intracranial extension not past chiasm.
T4d: intracranial extension past chiasm.
Regional lymph nodes (N)
NX: regional lymph nodes cannot be assessed.
N0: no regional lymph node involvement.
N1: regional lymph node involvement (preauricular, submandibular, or cervical).
N2: distant lymph node involvement.
Distant metastasis (M)
M0: no distant metastasis.
M1: systemic metastasis.
M1a: single lesion to sites other than CNS.
M1b: multiple lesions to sites other than CNS.
M1c: prechiasmatic CNS lesions.
M1d: postchiasmatic CNS lesions.
M1e: leptomeningeal and/or CSF involvement.
Pathologic classification (tumor-node-metastasis staging by pathology [pTNM])
Primary tumor (pT)
pTX: primary tumor cannot be assessed.
pT0: no evidence of primary tumor.
pT1: tumor confined to eye with no optic nerve or choroidal invasion.
pT2: tumor with minimal optic nerve and/or choroidal invasion.
pT2a: tumor superficially invades optic nerve head but does not extend past lamina cribrosa or tumor shows focal choroidal invasion.
pT2b: tumor superficially invades optic nerve head but does not extend past lamina cribrosa and shows focal choroidal invasion.
pT3: tumor with significant optic nerve and/or choroidal invasion.
pT3a: tumor invades optic nerve past lamina cribrosa but not to surgical resection line or tumor shows massive choroidal invasion.
pT3b: tumor invades optic nerve past lamina cribrosa but not to surgical resection line and shows massive choroidal invasion.
pT4: tumor invades optic nerve to resection line or shows extraocular extension elsewhere.
pT4a: tumor invades optic nerve to resection line but no extraocular extension identified.
pT4b: tumor invades optic nerve to resection line and extraocular extension identified.
Regional lymph nodes (pN)
pNX: regional lymph nodes cannot be assessed.
pN0: no regional lymph node involvement.
pN1: regional lymph node involvement (preauricular, cervical).
N2: distant lymph node involvement.
Distant metastasis (pM)
cM0: no metastasis.
pM1: metastasis to sites other than CNS.
pM1a: single lesion.
pM1b: multiple lesions.
pM1c: CNS metastasis.
pM1d: discrete masses without leptomeningeal and/or CSF involvement.
pM1e: leptomeningeal and/or CSF involvement.
Principles of treatment
Treatment of retinoblastoma is designed to save life and preserve vision, and thus needs to be individualized. Factors that need to be considered include unilaterality or bilaterality of the disease, potential for preserving vision, and intraocular and extraocular staging.
Surgery
Enucleation is indicated for large tumors filling the vitreous, for which there is little or no likelihood of restoring vision, and in cases of tumor presence in the anterior chamber, or in the presence of neovascular glaucoma. Enucleation should be performed by an experienced ophthalmologist; the eye must be removed intact, without seeding the malignancy into the orbit, and avoiding globe perforation. In addition, a long section (10–15 mm) of the optic nerve needs to be removed with the globe for optimal staging and best outcome when optic nerve involvement is present. An orbital implant is usually fitted during the same procedure, and the extraocular muscles can be attached to it. A prosthetic eye, usually made of a hard plastic, is later fitted in the orbital socket. For patients presenting with orbital disease, a judicious use of chemotherapy, surgery (enucleation), and radiation therapy results in good tumor control, avoiding the need for orbital exenteration.
Focal Therapies
Focal treatments are used for small tumors (<3–6 mm), usually in patients with bilateral disease, and in combination with chemotherapy. Photocoagulation with argon laser is used for the treatment of tumors situated at or posterior to the equator of the eye, as well as for the treatment of retinal neovascularization caused by radiation therapy. This technique is limited to tumors with a base no wider than 4.5 mm and no greater than 2.5 mm in thickness. The treatment is designed to coagulate all blood supply to the tumor. Cryotherapy is used for the treatment of small equatorial and peripheral lesions, measuring no more than 3.5 mm in base width and no more than 2 mm thickness. One or 2 monthly sessions of triple freeze and thaw are performed, and tumor control rates are usually excellent. In addition, an important focal method is transpupillary thermotherapy, which applies focused heat at subphotocoagulation levels, usually with a diode laser. In thermotherapy, the goal is to deliver a temperature of 42 ° C to 60 ° C for 5 to 20 minutes to the tumor, sparing retinal vessels from photocoagulation. The use of focal treatments is especially important in conjunction with chemotherapy, because the two treatment modalities seem to have a synergistic effect. In general, local control rates of 70% to 80% can be achieved. Complications of focal treatments include transient serous retinal detachment, retinal traction and tears, and localized fibrosis.
Chemotherapy
Chemotherapy is indicated in patients with extraocular disease, in the subgroup of patients with intraocular disease with high-risk histologic features after enucleation, and in patients with intraocular disease, in conjunction with aggressive focal therapies, for ocular preservation. Agents effective in the treatment of retinoblastoma include platinum compounds, etoposide, cyclophosphamide, doxorubicin, vincristine, and ifosfamide. For ocular preservation, chemotherapy is given with the objective of attaining a maximal cytoreduction that can be further consolidated with focal treatments or radiation therapy. In this setting, chemotherapy has traditionally been administered intravenously, but in recent years direct ocular delivery via catheterization of the ophthalmic artery is becoming more popular (discussed later).
Radiotherapy
Retinoblastoma is a very radiosensitive tumor. Radiotherapy in combination with focal treatments can provide excellent tumor control. However, because radiation therapy increases the risk of second malignancies, contemporary management of intraocular retinoblastoma is designed to avoid or delay its use; the role of irradiation is mainly as salvage management for eyes that have failed chemotherapy and focal treatments, usually because of progression of vitreous and subretinal seeding. Radiation therapy can be delivered in the form of brachytherapy or external beam radiation. Brachytherapy is used for the control of small tumors, usually in conjunction with other therapies; implants of radioactive material are placed as episcleral plaques for a period of time to deliver high doses of radiation well focused to the tumor, sparing the normal structures. Most implants now use iodine-125 ( 125 I). Many other agents can be used, such as radioactive gold, cobalt, palladium, and ruthenium. External beam technique is used for treatment of the entire eye globe for ocular salvage, or for the management of extraocular disease to the orbit, central nervous system (CNS), or metastatic sites. Several techniques can be used, usually through lateral or anterior fields. Recommended total doses are 40 Gy to 45 Gy, in 180-cGy to 200-cGy fractions, although doses of 36 Gy and even lower may be effective in conjunction with other techniques. Photons are commonly used; however, the use of proton therapy has significant advantages for patients with bilateral disease in terms of potentially lower risk of second malignancies.
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